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  • Updated 10.10.2021
  • Released 01.17.2013
  • Expires For CME 10.10.2024

Leukodystrophies

Introduction

Overview

Leukodystrophies are a heterogeneous group of genetic disorders that affect the white matter of the central nervous system, with some entities also affecting the peripheral nervous system. There are over 30 different leukodystrophies, with an overall population incidence of 1 in 7663 live births (09; 57). They are now most commonly grouped based on the initial pattern of central nervous system white matter abnormalities on neuroimaging. Every leukodystrophy is unique in its clinical presentation and pathologic mechanisms, but there is also significant variability within each leukodystrophy, which poses clinical challenges. However, as our knowledge increases, clinical approaches to patients with leukodystrophies and novel therapeutics are constantly being innovated. Nevertheless, early diagnosis with genetic counseling remains one of the cornerstones of patient care.

Key points

• Leukodystrophies are defined as genetic disorders that primarily affect the white matter predominantly of the central nervous system; these disorders have either glial cell or myelin sheath abnormalities.

• There are other entities called genetic leukoencephalopathies that also are characterized predominantly with white matter abnormalities but do not meet the criteria for being defined as a leukodystrophy.

• The pattern of abnormalities on brain MRI is one of the most useful diagnostic tools.


• Novel therapies such as gene therapy and small molecule therapies affecting change to the CNS are under investigation.

Historical note and terminology

The first leukodystrophy was identified in the early 20th century. Both Nissl and Alzheimer coincidentally reported metachromatic staining of the white matter of an adult patient diagnosed with what we now call metachromatic leukodystrophy (04; 39). Globoid cell leukodystrophy, or Krabbe disease, was described in 1916 when Hallervorden suggested that globoid cells may contain kerasin or cerebroside. Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (05), and galactocerebroside was the only glycolipid that could produce globoid cells when experimentally injected into the central nervous system of animals. Until the early 1990s, the known leukodystrophies were metachromatic leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, and 2 forms of adult-onset autosomal dominant leukodystrophies (02).

One difficulty has been in differentiating which clinical syndrome qualifies as a leukodystrophy rather than a leukoencephalopathy. Over the years, multiple terminologies, including demyelination, dysmyelination, leukoencephalopathy, and leukodystrophy, have been used for the varied spectrum of clinical and radiological phenotypes with white matter involvement. Most recently, a consensus of experts in the field better defined the terms. Leukodystrophies are defined as “heritable disorders affecting the white matter of the central nervous system with or without peripheral nervous system involvement with common glial cell or myelin sheath abnormalities.” Disorders with significant white matter abnormality that does not meet the inclusion criteria for leukodystrophies are considered genetic leukoencephalopathies (57).

The consensus definition does emphasize that CNS diseases in which neuropathology shows primary involvement of neurons in the cerebral cortex or other gray matter structures, but in which brain MRI also detects significant abnormalities of white matter, should not be characterized as leukodystrophies. For example, disorders like San Filippo disease, Batten disease, etc., which can cause secondary white matter abnormalities, are not defined as leukodystrophies. Similarly, disorders that are primary vasculopathies resulting in white matter abnormalities are also not classified as leukodystrophies (eg, COL4A2-, COL4A1-, and CADASIL-related disorders). Interestingly, the definition does not discriminate based on clinical presentation. Many of the leukodystrophies do not present as such (eg, adrenomyeloneuropathy, PLP1 presenting as spastic paraplegia). Also, the clinical progression does not need to be progressive to meet the definition of leukodystrophy; for example, megalencephalic leukoencephalopathy with subcortical cysts caused by HEPACAM mutations can be characterized by clinical improvements.

Table 1. Disorders Characterized As Leukodystrophy Under 2015 GLIA Definition

Name of disorder

Mode of inheritance

Biochemical testing

Molecular genetics

18q minus syndrome

Most often de novo deletion; may be inherited



Adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (including hereditary diffuse leukoencephalopathy with spheroids and pigmentary type of orthochromatic leukodystrophy with pigmented glia)

AD


CSF1R

Aicardi-Goutières syndrome

Usually AR; may be AD

In CSF: lymphocytosis, increased INF-alpha, increased pterins

In plasma: increased liver enzymes, thrombocytopenia

TREX 1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1

Alexander disease

AD


GFAP

Autosomal dominant leukodystrophy with autonomic disease

AD


LMNB1

Canavan disease

AR

In urine and CSF: increased N-acetylaspartic acid

ASPA

Cerebrotendinous xanthomatosis

AR

In plasma: increased cholestanol, normal to low cholesterol, increased lactate

In bile, urine, and plasma: increased bile alcohols and glyconjugates

In CSF: increased cholestanol and apolipoprotein B

CYP27A1

Chloride ion channel 2-related leukoencephalopathy with intramyelinic edema

AR


CLCN2

eIFB2 -related disorder (vanishing white matter disease or childhood ataxia with central nervous system hypomyelination)

AR

In CSF: increased glycine

EIF2B1-5

Fucosidosis

AR

On urinary oligosaccharide assay: increased fucose-containing glyconjugates

In leukocytes and fibroblasts: decreased alpha-fucosidase activity

FUCA1

Globoid cell leukodystrophy (Krabbe disease)

AR

In leukocytes: decreased galactocerebrosidase activity

Plasma: increased psychosine

GALC

Hypomyelination with atrophy of the basal ganglia and cerebellum

AD


TUBB4A

Hypomyelination with brainstem and spinal cord involvement and leg spasticity

AR


DARS1

Hypomyelination with congenital cataract

AR


FAM126A

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

AR


DARS2

Leukoencephalopathy with thalamus and brainstem involvement and high lactate

AR


EARS2

Megalencephalic leukoencephalopathy with subcortical cysts

AR (MLC1 and MLC2A)
AD (MLC2B)


MLCI, MLC2A, MLC2B

Metachromatic leukodystrophy

AR

In leukocytes and fibroblasts: decreased arylsulfatase activity

In urine: increased sulfatides

ARSA

Oculodentodigital dysplasia

Usually AD, may be AR


GJA1

Pelizaeus Merzbacher disease

X-linked


PLP1

Pelizaeus Merzbacher like-disease

AR


GJC2

Peroxisomal biogenesis disorders (including Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease)

AR

Plasma VLCFA, phytanic and pristanic acid; plasma and urine pipecolic acid and bile acids help distinguish different forms of peroxisomal disorders

PEX genes

Pol III-related disorders (4H syndrome: hypomyelination, hypodontia, hypogonadotropic hypogonadism)

AR


POLR3A, POLR3B

Polyglucosan body disease

AR

In leukocytes: decreased 1,4 alpha glucan branching enzyme 1 activity

Histopathologic examination of muscles, nerve, axillary skin: pathologic polyglucosan accumulation

GBE1

RNAse T2 deficient leukoencephalopathy

AR


RNASET2

Sialic acid storage disorders (Salla disease, infantile sialic acid storage disease, and intermediate form)

AR

In urine and fibroblasts: increased free sialic acid

SLC17A5

Single enzyme deficiencies of peroxisomal fatty acid beta oxidation (including only D-bifunctional protein deficiency; sterol carrier protein deficiency; peroxisomal acyl-CoA-oxidase deficiency)

AR

Plasma VLCFA, phytanic and pristanic acid; plasma and urine pipecolic acid and bile acids help distinguish different forms of peroxisomal disorders

DBP deficiency: HSD17B4

SCPx deficiency: SCP2

Acyl-Coa-oxidase deficiency: ACOX1

Sjögren-Larsson syndrome

AR

In urine: abnormal metabolites of leukotriene B4

In fibroblasts and leukocytes: decreased fatty aldehyde dehydrogenase activity or of fatty alcohol: NAD reductase activity

ALDH3A2

SOX10-associated PCWH (peripheral demyelinating neuropathy, central demyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease)

AD


SOX10

X-linked adrenoleukodystrophy

X-linked

On plasma VLCFA assay: increased C26:0, ratio of C24:0 to C22:0, ratio of C26:0 to C22:0

ABCD1


(57) AD = autosomal dominant, AR = autosomal recessive, VLCFA = very long-chain fatty acid

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